Impact of dosing strategy on clinical outcomes of patients with lupus nephritis initially treated with lower-than-recommended-dose cyclophosphamide.

Aim: Cyclophosphamide is the mainstay treatment for patients with lupus nephritis (LN); it can be prescribed at lower doses than the recommended regimen to avoid side effects. We aimed to investigate the impact of cyclophosphamide dosing strategies on treatment outcomes of patients with LN initially treated with a lower-than-recommended dose. Methods: We retrospectively reviewed patients with proliferative LN (class III, IV, or mixed) initially treated with lower-than-recommended-dose cyclophosphamide. Patients who received a titrated dose of cyclophosphamide ≥0.5 g/m2 were categorized into the titrate group, while those who received doses <0.5 g/m2 were categorized into the non-titrate group. The primary outcome was primary renal response (PRR) at 52 weeks. Results: Of the 78 patients included, 47 were assigned to the titrate group and 31 to the non-titrate group. The titrate group had a higher proportion of PRR achievement (23 of 47 patients [48.9 %] vs. 7 of 31 patients [22.6 %] in the non-titrate group). After adjusting for potential confounders, a baseline urinary protein-to-creatinine ratio ≥3 g/g (OR, 0.3; 95 % CI, 0.1-0.9; P = 0.030), and titrating the dose of cyclophosphamide to ≥0.5 g/m2 (OR, 4.7; 95 % CI, 1.5-15.2; P = 0.010) were independent factors for PRR. Additionally, the titrate group had a lower rate of infection (8 of 47 patients [17.0 %] vs. 12 of 31 patients [38.7 %], respectively; OR, 0.3; 95 % CI, 0.1-0.9; P = 0.036) and death associated with LN (4 of 47 patients [8.5 %] vs. 8 of 31 patients [25.8 %], respectively; OR, 0.3; 95 % CI, 0.1-0.9; P = 0.047) compared with the non-titrate group. LN flare and the need for rescue therapy did not differ between the groups. Conclusion: For patients with LN initially treated with lower-than-recommended-dose cyclophosphamide, titration of the cyclophosphamide dose ≥0.5 g/m2 was beneficial on renal response, while reducing infection leading to hospitalization and LN-associated death.

Attainment of EULAR/ERA-EDTA targets of therapy with current immunosuppressive regimens and adjustments in treatment: a multicentre, real-life observational study.

OBJECTIVE: To estimate real-life European Alliance of Associations for Rheumatology (EULAR)/European Renal Association (ERA)-European Dialysis and Transplantation Association (EDTA) response rates and predictors for no response in patients with lupus nephritis (LN) managed with conventional immunosuppressive therapies. METHODS: Ambidirectional cohort study of patients with new-onset LN (period 2014-to date). Response rates in the first year were calculated, and all treatment modifications were recorded. Univariate and multivariate regression analyses were performed to assess determinants of failure to respond at 12 months. RESULTS: 140 patients were included (81.4% women, median (IQR) age at LN diagnosis 38 (22) years). Among them, 32.1% presented with nephrotic range proteinuria, 28.6% with glomerular filtration rate <60 mL/min, 76.6% had proliferative and 19.7% class V LN. Initial treatment consisted of cyclophosphamide in 51.4% of patients (84.7% high-dose, 15.3% low-dose) and mycophenolate in 32.1%. 120 patients had available data at 12 months. EULAR/ERA-EDTA renal response rates at 3, 6 and 12 months were achieved by 72.6%, 78.5% % and 69.2% of patients, respectively. In multivariate analysis, increased Chronicity Index at baseline was associated with failure to achieve either complete or partial response at 12 months (OR 2.26, 95% CI 1.35 to 3.77). Notably, 20% of patients required treatment modifications due to suboptimal response during the first 12 months, with the addition of or switch to a different immunosuppressive drug in seven and nine patients, respectively. CONCLUSIONS: More than two-thirds of patients with LN attain EULAR/ERA-EDTA response rates by 12 months, but 20% require therapy modifications within this time period. Patients with increased chronicity in baseline biopsy, when combined with histological activity, are at higher risk for a lack of clinical response.

The hepatoprotective effects of sitagliptin against cyclophosphamide-induced hepatotoxicity in rat.

Hepatotoxicity is a serious side effects of cyclophosphamide. Thus, the present research investigates the protective properties of sitagliptin against cyclophosphamide-induced hepatotoxicity. Fifty male rats were randomly divided into five groups. They were pre-treated with either sitagliptin or normal saline once a day for the first ten days of the study. To induce acute hepatotoxicity, cyclophosphamide (200 mg/kg, i.p) was injected only one time and 45 min after the last dose of sitagliptin. The rats were sacrificed on the 11th day, and their blood and liver were collected for biochemical, gene expression, and histopathological assessments. Our results showed that cyclophosphamide induced obvious liver toxicity as marked by an increase in serum levels of alanine transaminase and aspartate transaminase, reduced serum albumin and total protein levels, in addition to histopathological changes. The malondialdehyde, tumor necrosis factor-α, and interleukin-6 levels were also elevated and total antioxidant capacity declined in serum and hepatic homogenates. Sitagliptin magnificently attenuated the cylophosphamide-induced histological alterations, improved liver function tests, enhanced total antioxidant capacity, and decreased malondialdehyde, tumor necrosis factor-α, and interleukin-6 in the blood and hepatic tissues. These findings suggest that sitagliptin has hepatoprotective activity against cyclophosphamide toxicity, which may be due to its antioxidant and anti-inflammatory effects.

Therapeutic effects of curcumin nanoemulsion on cyclophosphamide-induced testicular toxicity in adult male mice.

Objective: Several chemotherapeutic agents, including cyclophosphamide (CP) and busulfan, have been shown to interfere with spermatogenesis. Accordingly, the main objective of this study was to evaluate the potential therapeutic effects of curcumin nanoemulsion (CUR-NE) on spermatogenesis in mice with CP-induced testicular toxicity. Methods: A total of 28 adult male mice were equally divided into four groups: control, CUR-NE (30 mg/kg, daily for 5 weeks), CP (200 mg/kg, single dose), and CP+CUR-NE. Each group was evaluated regarding sperm parameters, DNA fragmentation index, chromatin maturation, reactive oxygen species (ROS) levels, and histological parameters of the testes. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone, and testosterone were also assessed in all groups. Results: In CP-induced mice, CUR-NE treatment significantly improved sperm parameters, including total sperm count, motility, morphology, and DNA integrity. CUR-NE administration was also associated with significantly higher serum levels of testosterone and FSH, as well as testis weight and volume, in the mice treated with CP. Furthermore, CUR-NE treatment significantly increased the number of spermatogonia, primary spermatocytes, round spermatids, and Leydig cells in the testicular tissue of these animals. A marked reduction in ROS levels in the testes tissue was observed following administration of CUR-NE to CP-induced mice. Conclusion: CUR-NE appears to promote spermatogenesis in mice with CP-induced testicular toxicity by reducing ROS levels, improving testicular stereological parameters, and strengthening the reproductive hormone profile.

Impact of cyclophosphamide on the morphological and histological changes in polyglycolic acid spacers.

In radiotherapy for pediatric abdominal tumors, determining the effect of concurrent chemotherapy on polyglycolic acid (PGA) spacers is crucial; yet this effect has not been validated. Therefore, we aimed to evaluate the impact of cyclophosphamide (CPA) chemotherapy on the PGA spacer using a rat model. Twenty-four rats were implanted with the spacer, and morphological changes in the spacer were assessed on CT for both the CPA-dosed group (40 mg/kg) and the control group. The size and volume of the spacer were quantified using CT, while the degree of adhesion and microscopic examination of the tissue were determined using pathology specimens. Morphologically, the size of the spacer decreased over time in both the CPA-dosed and control groups, with no significant differences observed between groups. No significant differences in adhesion were observed between the two groups. Macrophages were observed around the PGA fibers, suggesting their involvement in the degradation of the PGA spacer. These results suggest that CPA does not cause significant clinically problematic degradation or adverse tissue reactions to the PGA spacer. This study reinforced the benefits of PGA spacers; however, future research focusing on in vivo longitudinal monitoring of individual rats, as well as on humans, is required.

Divine noni's protective impact on Swiss albino mice's short-term memory impairment caused by cyclophosphamide: A behavioral and biochemical approach.

Cyclophosphamide (CYL) is a first-line cancer chemotherapeutic agent widely used for the treatment of cancer that has severe toxic effects. The primary mechanism by which CYL induces toxicity through free radical generation. Morinda citrifolia (Noni) fruit juice is an herbal remedy documented to have antioxidant properties. The aim of the current study was to investigate the protective effect of noni against CYL-induced memory impairment in Swiss albino mice. Treatment schedule: Group 1: Normal: Received vehicle; Group 2: CYL treatment: Received CYL (40.0 mg/kg b.w. i.p.) on day one; Group 3: NJ treatment: Received NJ (360 mg/b.w. p.o.) once daily for 14 days. Group 4: DNG treatment: DNG (360 mg/b.w. p.o.) once daily for 14 days, Group 5: NJ + CYL treatment: Received CYL (40.0 mg/kg b.w. i.p.) on day one and after half an hour of received NJ (360 mg/b.w. p.o.) once daily for 14 days. Group 6: DNG + CYL treatment: Received CYL (40.0 mg/kg b.w. i.p.) on day one and after half an hour received DNG (360 mg/b.w. p.o.) once daily for 14 days. Mice were subjected to the Morris water maze (MWM) challenge for two weeks as part of a behavioral study. Short-term memory impairment was observed in the behavioral activity of CYL-treated mice in the MWM test in the 1st week trial, and this effect was reversed in the 2nd week trial in the combination treatment group. The behavioral analysis proved that noni supplementation reduced the risk of memory impairment caused by CYL. Biochemical analysis revealed that CYL markedly increased the levels of AChE and MDA in brain tissue. Similarly, decreases in the levels of antioxidants, i.e., GSH, CAT, SOD and GST, were detected in the brain tissue of the mice exposed to CYL. Qualitative and quantitative examinations of histopathological examination of the mouse hippocampus supported the above findings. The results demonstrated that noni supplement therapy reversed the changes in the MDA, AChE, and antioxidant enzyme levels while improving the behavioral and histological alterations caused by CYL. Long-term hippocampal growth and memory are unaffected, suggesting that CYL is less harmful. According to our research, supplementing with noni in conjunction with CYL may be a helpful treatment strategy for treating memory impairment caused by CYL.

Efficacy and safety of oral cyclophosphamide versus mycophenolate mofetil in childhood nephrotic syndrome: an open-label comparative study.

INTRODUCTION: There is a scarcity of research comparing the efficacy of cyclophosphamide and mycophenolate mofetil in childhood nephrotic syndrome. The aim was to evaluate the efficacy and safety of oral cyclophosphamide (CYC) and mycophenolate mofetil (MMF) in children with steroid-sensitive nephrotic syndrome in terms of the proportion of children who have been off steroids for at least 6 months without proteinuria (responders). METHODS: This open-label retrospective-prospective comparative study was conducted in a pediatric nephrology clinic of a referral center for children between 1 and 18 years of age with FR/SD nephrotic syndrome. Group A consisted of patients who received oral cyclophosphamide (100, 25% female) at a dose of 2-2.5 mg/kg once daily for a period of 8-12 weeks. Group B consisted of patients who received oral mycophenolate mofetil (n = 61, 18% female) (dose: 800-1200 mg/m2) for at least 12 months. Responders were defined as children who were off steroids for at least 6 months along with absence of proteinuria. RESULTS: In the CYC group, 50% of the patients were responders, whereas 54% of the patients in the MMF group were responders (p = 0.614). The time to first relapse with CYC was 7 months (IQR 5.25-11) compared to 7 months (IQR 3.5-12) with MMF (p = 0.092). The relapse rate in the CYC group was 1.77 relapses per patient-year compared to 1.295 relapses per patient-year in the MMF group. The difference in relapse rate was significant (-0.474; 95% CI, 0.09 to 0.86 relapses/person-year) (p value = 0.009). Multivariate analysis revealed that an age of less than 5 years at the start of treatment was a significant factor for a better response to MMF (p value = 0.039, OR = 2.988, CI -1.055-8.468). CONCLUSIONS: The efficacy of MMF was similar to that of CYC in terms of response (6 months without steroids) in children with FR/SD nephrotic syndrome. MMF showed a favorable response in terms of the frequency of relapse and treatment failure. REGISTRATION OF THE STUDY WITH CLINICAL TRIALS REGISTRY OF INDIA: ( http://ctri.nic.in ;CTRI/2021/06/034421) (Dt: 28/06/2021).

Histological assessment for investigation of dose-dependent ovarian toxicity of cyclophosphamide in the rat.

Background: Cyclophosphamide (CPA) have significant effects on ovarian follicles which lead to ovarian toxicity and impair the normal female reproductive function. This study aimed to evaluate the dose-dependent effects of CPA on rat follicle numbers. Methods: The experimental groups consisted of rats administered a single intraperitoneal injection of CPA at doses of either 50, 75,150, or 200 mg/kg followed by daily doses of 8 mg/kg for 14 days and control group given no treatment. After the treatment period, the histological evaluation was done. Results: Primordial and primary follicles were affected by all doses of CPA, but differential follicle counts revealed that graaf and preantral follicles were most sensitive to CPA, followed by primary and primordial follicles. The greatest reduction in all type of studied follicles caused by CPA doses of 50 mg/kg. Conclusion: Differential follicle counts revealed that CPA-induced ovarian toxicity is exhibited in structural feature of the ovary, particularly in destruction of graaf and preantral follicles in a dose-dependent manner so that the highest decrease in all type of studied follicles caused by 50 mg/kg of CPA and is suggested as the best concentration for ovotoxicity induction. These findings give insight into ovarian response to structural disruption of folliculogenesis.

Yam protein ameliorates cyclophosphamide-induced intestinal immunosuppression by regulating gut microbiota and its metabolites.

Yam is a dual-purpose crop used in both medicine and food that is commonly used as a dietary supplement in food processing. Since yam proteins are often lost during the production of yam starch, elucidating the functionally active value of yam proteins is an important guideline for fully utilizing yam in industrial production processes. This study aimed to explore the potential protective effect of yam protein (YP) on cyclophosphamide (CTX)-induced immunosuppression in mice. The results showed that YP can reduce immune damage caused by CTX by reversing immunoglobulins (IgA, IgG and IgM), cytokines (TNF-α, IL-6, etc.) in the intestines of mice. Moreover, YPs were found to prevent CTX-induced microbiota dysbiosis by enhancing the levels of beneficial bacteria within the microbiome, such as Lactobacillus, and lowering those of Desulfovibrio_R and Helicobacter_A. Metabolomics analyses showed that YP significantly altered differential metabolites (tryptophan, etc.) and metabolic pathways (ABC transporter protein, etc.) associated with immune responses in the gut. Furthermore, important connections were noted between particular microbiomes and metabolites, shedding light on the immunoprotective effects of YPs by regulating gut flora and metabolism. These findings deepen our understanding of the functional properties of YPs and lay a solid foundation for the utilization of yam.

Immune and microbiome modulatory effects of Limosilactobacillus fermentum NCDC 400 in an immunocompromised mouse model.

The present study was aimed to assess and validate the safety and functional efficacy of an indigenous probiotic strain Limosilactobacillus fermentum NCDC 400 (hereafter, LFN400) in an immunocompromised murine model. The study included four groups; a normal control (NC) group without immune suppression; an experimental model control (MC) with immune suppression induced via intraperitoneal cyclophosphamide (Cy) administration; and two MC groups orally administered with either low dose (LD) or high dose (HD) of LFN400 at dose 108 and 1010 CFU/mouse/day, respectively, for 15-days. Both control groups received normal saline as placebo control. LFN400 improved specific experimental characteristics including hematological and serum biochemical markers. Compared to MC group, LFN400-fed groups showed markedly (P < 0.05) decreased arrays of detrimental caecal enzymes. We did not observe instances of bacterial translocation of LFN400 from gut to bloodstream or extra-intestinal organs. LFN400 intake significantly (P < 0.05) enhanced spleen cell differentiation, immune and oxidative stress markers, and restored Cy-induced histopathological changes in multiple tissues, including the spleen. There was no genotoxic effect of LFN400 on bone marrow cells. Although not statistically significant, LFN400 feeding moderately increased gut microbiome diversity, supporting the growth of beneficial saccharolytic microorganisms and reducing the presence of pathobionts. The findings demonstrate that the probiotic strain LFN400 possesses in vivo safety and immunomodulatory potency and thus should be considered a potential candidate for future human clinical studies.

Bone marrow mesenchymal stem cells expressing Neat-1, Hotair-1, miR-21, miR-644, and miR-144 subsided cyclophosphamide-induced ovarian insufficiency by remodeling the IGF-1-kisspeptin system, ovarian apoptosis, and angiogenesis.

Ovarian insufficiency is one of the common reproductive disorders affecting women with limited therapeutic aids. Mesenchymal stem cells have been investigated in such disorders before yet, the exact mechanism of MSCs in ovarian regeneration regarding their epigenetic regulation remains elusive. The current study is to investigate the role of the bone marrow-derived mesenchymal stem cells (BM-MSCs) lncRNA (Neat-1 and Hotair1) and miRNA (mir-21-5p, mir-144-5p, and mir-664-5p) in mitigating ovarian granulosa cell apoptosis as well as searching BM-MSCs in altering the expression of ovarian and hypothalamic IGF-1 - kisspeptin system in connection to HPG axis in a cyclophosphamide-induced ovarian failure rat model. Sixty mature female Sprague Dawley rats were divided into 3 equal groups; control group, premature ovarian insufficiency (POI) group, and POI + BM-MSCs. POI female rat model was established with cyclophosphamide. The result revealed that BM-MSCs and their conditioned media displayed a significant expression level of Neat-1, Hotair-1, mir-21-5p, mir-144-5p, and mir-664-5p. Moreover, BM-MSCs transplantation in POI rats improves; the ovarian and hypothalamic IGF-1 - kisspeptin, HPG axis, ovarian granulosa cell apoptosis, steroidogenesis, angiogenesis, energy balance, and oxidative stress. BM-MSCs expressed higher levels of antiapoptotic lncRNAs and microRNAs that mitigate ovarian insufficiency.

Uniform graft-versus-host disease prophylaxis using post-transplantation cyclophosphamide, methotrexate, and cyclosporine following peripheral blood hematopoietic stem cell transplantation from matched and haploidentical donors for transfusion-dependent thalassemia: a retrospective report from the BMF-WG of Hunan province, China.

BACKGROUND: Although the survival of patients with transfusion-dependent thalassemia (TD-TM) is reportedly inferior after haploidentical transplantation, the heterogeneity of transplantation approaches in studies suggests the need to assess the effect of one given conditioning regimen on matched and haploidentical transplantation outcomes. OBJECTIVE: A novel PTCy-based approach for patients with TD-TM undergoing haploidentical HSCT was reported in our prior study. We aimed to retrospectively evaluate the real-world efficacy and safety of GvHD prophylaxis in patients with TD-TM after HSCT from matched donors and haploidentical donors (HIDs). STUDY DESIGN: This was a retrospective multicenter study. Of 238 patients with TD-TM who underwent HSCT, 160 underwent peripheral blood HSCT, using uniform GvHD prophylaxis with PTCy, methotrexate, and cyclosporine, at member centers of the Bone Marrow Failure Working Group of Hunan Province between 2019 and 2023. RESULTS: The median age of the cohort was 6 years (95% confidence interval [CI], 6-7 years) at transplantation. Of 160 donors, 99 (61.9%) were haploidentical family members, and the others were matched donors (13 matched siblings, 48 matched or mismatched unrelated donors). The engraftment rate was 98.8% (95% CI: 96.1%-97.7%). HSCT from HIDs had a lower risk of mixed chimerism (HR 0·078, p=0.022). Within 100 days after transplantation, 31 patients (19.6%, 95% CI: 14.0%-26.3%) had grade II-IV acute GvHD, 9 of whom had grade III-IV acute GvHD (5.7%, 95% CI: 2.9%-10.1%). HIDs were significantly associated with a higher risk of grade II-IV acute GvHD (HR 3.973, p = 0.009). Nineteen patients (11.9%, 95% CI: 7.6%-17.6%) developed late acute GvHD after a median of 516 days (95% CI: 407-709 days). Twenty-six patients (16.5%, 95% CI: 11.3%-22.8%) exhibited any one of the diagnostic, distinctive, or atypical features of chronic GvHD according to the 2014 NIH criteria after a median of 690 days (95% CI: 496-902 days). Among these, 7 had NIH-defined chronic GvHD, 14 had only one distinctive sign with no histological evidence, and 5 had only atypical chronic GvHD signs. Of the 26 patients, 5 were classified as having overlap syndrome. Of 21 patients who were classified as having NIH-defined and potential chronic GvHD, 3 had moderate chronic GvHD, whereas 1 had severe chronic GvHD. Logistic regression analyses identified that grade II-IV acute GvHD independently predicted subsequent chronic GVHD (HR 3.920, p=0.006). The rates of chronic GvHD were similar between the matched and HID groups. Thalassemia-free survival (TFS) and event-free survival (EFS) were 97.5% (95% CI: 94.2%-99.2%) and 90.6% (95% CI: 85.4%-94.4%), respectively, after a median of 690 days (95% CI: 496-902 days). TFS rates were similar between the matched and HID groups (p = 0.549). The EFS rate was significantly higher in the matched group than in the HID group (p = 0.033). CONCLUSIONS: Our study suggests that when PTCy-based uniform GVHD prophylaxis is administered, HSCT from matched donors and HIDs results in a low incidence of severe GVHD and treatment-related mortality with satisfactory survival.

The Protective Effect of GnRH Agonist Triptorelin on the Histomorphometric Parameters of the Utero-ovarian Tissue in the Doxorubicin- and Cyclophosphamide-treated Mice.

One of the common side effects of chemotherapy drugs is ovarian failure and uterine dysfunction, which can occur after the administration of doxorubicin and/or cyclophosphamide. In clinics, gonadotropin-releasing hormone agonists (GnRHa) are used to modulate the toxic effect of chemotherapy and intercept infertility with some controversy and limited histological knowledge. This study aimed to evaluate the serological and histological features of protective effects of triptorelin, (GnRHa), on utero-ovarian tissue in the mice treated with cyclophosphamide and/or doxorubicin. Forty-eight female BALB/c mice were randomly divided into 8 groups as follows: Group I: normal saline; Group II: triptorelin; Group III: cyclophosphamide; Group IV: doxorubicin; Group V: cyclophosphamide + doxorubicin; and Groups VI, VII, and VIII: after injection of cyclophosphamide, doxorubicin, or cyclophosphamide + doxorubicin, administration of triptorelin (1 mg/kg; intraperitoneally) for 15 consecutive days, respectively. On the 21st day, the ovaries and uterine horns were dissected and weighed. Then, tissue processing and staining were performed for further histological and stereological studies. Triptorelin treatment in the damaged groups significantly increased the number of primordial and pre-antral follicles and granulosa cells. It decreased the number of atretic follicles compared to cyclophosphamide and/or doxorubicin-treated groups (P < 0.05). Triptorelin also significantly improved the volume of the ovary, cortex, medulla, oocytes in the primordial and antral follicles, uterus, endometrium, myometrium, uterine glands, and endometrial blood vessels in the damaged groups (P < 0.05). Triptorelin treatment prevents the destructive effects of cyclophosphamide and/or doxorubicin on utero-ovarian tissue.

Shikonin mitigates cyclophosphamide-induced cardiotoxicity in mice: the role of sirtuin-1, NLRP3 inflammasome, autophagy, and apoptosis.

OBJECTIVES: The aim of this study was to elucidate the protective potential of shikonin (SHK) on cyclophosphamide (CP)-induced cardiotoxicity in Swiss albino mice. METHODS: Mice received SHK in three different doses by oral gavage daily for 14 days and CP at 100 mg/kg, intraperitoneally once on the seventh day. On the 15th day, mice were euthanized, blood collected, and hearts were removed to estimate various biochemical and histopathological parameters. KEY FINDINGS: CP significantly increased serum lactate dehydrogenase, creatine kinase-MB, troponin I and NT pro-BNP, and cardiac malondialdehyde and decreased cardiac total antioxidant capacity and Nrf2, whereas increased inflammatory markers in the cardiac tissues. CP also caused hypertrophy and fibrosis in the cardiac tissues via activation of IL6/JAK2/STAT3 while depressed SIRT1 and PI3K/p-Akt pathway with consequent increased apoptosis and dysregulation of autophagy. SHK treatment reversed these changes in a dose-dependent manner and showed a significant protective effect against CP-induced cardiotoxicity via suppressing oxidative stress, inflammation, and apoptosis with modulation of autophagy via induction of SIRT1/PI3K/p-Akt signaling. CONCLUSIONS: Shikonin may be used as an adjuvant to cyclophosphamide in cancer treatment, but further research is needed to investigate its effects on cardiotoxicity in distinct animal cancer models.

Anti-PD-1 combined with hypomethylating agent and CAG regimen bridging to allogeneic hematopoietic stem cell transplantation: a novel strategy for relapsed/refractory acute myeloid leukemia.

Introduction: The prognosis of relapsed/refractory acute myeloid leukemia (r/rAML) is dismal, and allogeneic hematopoietic stem cell transplant (allo-HSCT) is a potential cure. Combining anti-PD-1, hypomethylating agent (HMA), and CAG (cytarabine, aclarubicin/idarubicin, granulocyte colony-stimulating factor) regimen has showed primary efficacy in r/rAML. However, pre-transplant exposure to anti-PD-1 may lead to severe graft-versus-host disease (GVHD). This preliminary study aimed to evaluate the safety and efficacy of allo-HSCT in r/rAML patients receiving the anti-PD-1+HMA+CAG regimen. Methods: Fifteen r/rAML patients (12 related haploidentical donors [HIDs], 2 matched siblings, 1 unrelated donor) received this regimen and subsequent peripheral blood HSCT. Results: Four patients with HIDs received a GVHD prophylaxis regimen consisted of Anti-thymocyte globulin and a reduced-dose of post-transplant cyclophosphamide. The median follow-up was 20.9 months (range, 1.2-34.2). The cumulative incidences of acute GVHD grade 2-4 and grade 3-4 were 40% and 13.3%, respectively. The 2-year incidence of moderate-to-severe chronic GVHD, non-relapse mortality, and relapse were 10%, 22.3%, and 22.5%, respectively. The 2-year overall survival and GVHD-free/relapse-free survival rates were 54% and 48.6%, respectively. No death or relapse was observed in the PTCy group. Conclusion: The anti-PD-1+HMA+CAG regimen bridging to allo-HSCT for r/r AML was tolerable with promising efficacy. GVHD prophylaxis with PTCy for HID-HSCT showed preliminary survival advantage.

Synergistic effects of herpes oncolytic virus and cyclophosphamide for recurrent malignant glioma: a narrative review.

Gliomas, comprising nearly 80% of brain malignancies, present a formidable challenge with glioblastomas being the most aggressive subtype. Despite multidisciplinary care, including surgery and chemoradiotherapy, the prognosis remains grim, emphasizing the need for innovative treatment strategies. The blood-brain barrier complicates drug access, and the diverse histopathology hinders targeted therapies. Oncolytic herpes viruses (oHSVs), particularly HSV1716, G207, and rQNestin34.5v, show promise in glioma treatment by selectively replicating in tumor cells. Preclinical and clinical studies demonstrate the safety and efficacy of oHSVs, with T-Vec being FDA-approved. However, challenges like viral delivery limitations and antiviral responses persist. The combination of oHSVs and combining cyclophosphamide (CPA) addresses these challenges, demonstrating increased transgene expression and viral activity. The immunosuppressive properties of CPA, particularly in metronomic schedules, enhance oHSV efficacy, supporting the development of this combination for recurrent malignant gliomas. CPA with oHSVs enhances viral oncolysis and extends survival. CPA's immunomodulatory effects, suppressing regulatory T cells, improve oHSV efficiency. While obstacles remain, this synergistic approach offers hope for improved outcomes, necessitating further research and clinical validation.

Suppression of glomerular damage, inflammation, apoptosis, and oxidative stress of acute kidney injury induced by cyclophosphamide toxicity using resveratrol in rat models.

Cyclophosphamide (CP) is a chemotherapy drug that can be used to treat different types of cancers, but its nephrotoxicity effects restrict its usage in clinical settings. Currently, we examined whether the polyphenolic antioxidant and anti-inflammatory compound, resveratrol (RES), can protect against CP-induced nephrotoxicity. Twenty male mature Sprague-Dawley rats were divided into 4 groups of equal size: control group, RES group which received RES (20 mg/kg) for 15 consecutive days, CP group which received CP as a single dose (150 mg/kg) on day 16, and CP+RES group which was similar of the RES and CP groups. Tissue samples were obtained for the stereological, immunohistochemical, biochemical, and molecular evaluations. Findings showed that the numerical density of glomerulus, total volumes and interstitial tissue volumes of kidney, antioxidative biomarkers concentrations (CAT, GSH, SOD), and expression levels of OCT2 gene were notably greater in the CP+RES group than the CP group (P<0.05). During treatment, there was a significant decrease in the serum levels of the urea and creatinine, the densities of apoptotic and inflammatory cells, as well as levels of MDA and proinflammatory cytokines (IL-1ß, TNF-α, and PFN1) in the CP+RES group than the CP group (P<0.05). We deduce that giving RES can suppress of glomerular damage, inflammation, apoptosis, and oxidative stress of acute kidney injury induced by CP toxicity.

Haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide for Fanconi anemia with/without anti-thymocyte globulin.

Background: We present comparative data of children with Fanconi anemia undergoing haploidentical hematopoietic stem cell transplantation (HSCT) with or without the addition of rabbit anti-thymocyte globulin (r-ATG) to the conditioning regimen. Patients and methods: This retrospective study included children with Fanconi anemia aged up to 18 years who underwent haploidentical HSCT between January 2015 and December 2022. The children were included in two cohorts in this study. Cohort 1 included children who received conditioning with fludarabine/cyclophosphamide/single fraction of 2 Gy TBI. The children in cohort 2 received the same conditioning along with r-ATG. Post-transplant cyclophosphamide was administered at a dose of 25 mg/kg on day3 and day4 in both cohorts. Results: A total of 35 children were included in the study, 25 in cohort 1 and 10 in cohort 2. Neutrophil engraftment was documented around day 14-16 post infusion in 21 children (84%) in cohort 1 and in 8 children (80%) in cohort 2. There was a significant difference in the incidence of the severity of graft versus host disease (GVHD) between the two cohorts (p = 0.003). In cohort 1, acute GVHD was documented in 17 children (68%), with grade 1/2 skin GVHD in 10 children, and grade 3/4 skin and gut GVHD in 7 children. Grade 4 gut GVHD was the cause of death in three children in cohort 1. In cohort 2, acute GVHD was documented in one child (10%) who had grade 4 skin and gut GVHD and succumbed to the above. Chronic GVHD was noted in nine (36%) children in cohort 1, and in one child (10%) in cohort 2. Cytomegalovirus reactivation was documented in 11 children (44%) in cohort 1 and three children (30%) in cohort 2. Overall survival was found to be 16/25 (64%) in cohort 1, with a median follow-up of 49 months, and 7/10 (70%) in cohort 2, with a median follow-up of 12 months. Conclusion: Serotherapy with r-ATG significantly reduced the incidence of GVHD from 68% to 10% in children with Fanconi anemia, with an increase in overall survival from 64% to 70%, although it did not affect graft failure. Further studies should focus on decreasing graft failure rates with early HSCT before multiple transfusions.

Treatment Approach for Advanced Systemic Light Chain Amyloidosis: A Case Report.

Systemic light chain amyloidosis is a rare and severe disorder characterized by amyloid fibril deposition in various tissues, often leading to organ failure. Early diagnosis is crucial but challenging due to diverse clinical manifestations. Our case report presents a complex case of systemic light chain amyloidosis in a 62-year-old patient with cardiac, renal, neurological, and gastrointestinal involvement. The patient's treatment with cyclophosphamide, bortezomib, dexamethasone, and intravenous daratumumab yielded significant improvement, aligning with recent studies. Following treatment, the patient improved from stage IV to stage II systemic light chain amyloidosis per the National Comprehensive Cancer Network (NCCN) guidelines, indicating a more favorable prognosis. Hence, the successful integration of daratumumab in our case underscores its potential as a valuable addition to the treatment regimen for advanced systemic light chain amyloidosis, showcasing significant improvements across multiple organ systems.

Silymarin mitigates toxic effects of cyclophosphamide on testicular tissue and sperm parameters in mice.

Cyclophosphamide, a chemotherapy drug, increases oxidative stress in sperm and testicular tissue. This study evaluated the effect of silymarin, a potent antioxidant, on the quality of sperm and testicular tissue in mice treated with cyclophosphamide. NMRI adult male mice were divided into four groups: control; cyclophosphamide (intraperitoneal injection, 100 mg/kg, once a week); cyclophosphamide + silymarin; and silymarin (intraperitoneal injection, 200 mg/kg, every other day). After a 35-day treatment period, the caudal region of the epididymis was examined for sperm parameters, the right testis was used for stereological studies, and the left testis was used to assess biochemical factors. The data were statistically analyzed using SPSS software, one-way ANOVA and Tukey's test. In the cyclophosphamide group, there was a significant reduction in the mean total volume of testicular tissue, the average volume of seminiferous tubules and their components, and the average volume of interstitial tissue. Additionally, there was a notable decrease (p < 0.001) in the average number of Leydig cells, Sertoli cells, and sperm parameters. The mean concentration of testosterone hormone (p < 0.05) and total antioxidant capacity (TAC) level (p < 0.01) also significantly decreased, while the malondialdehyde (MDA) level increased significantly (p < 0.05). However, these adverse changes were mitigated in the cyclophosphamide + silymarin group compared to the cyclophosphamide group. Our results showed that silymarin as an antioxidant can mitigate the adverse effects of cyclophosphamide on testicular tissue and sperm parameters.